Congenital Patterned Leukodermas

The following congenital hypopigmentary diseases result from a failure of pigment cells (melanocytes) in the skin, eyes, and/or ears to become completely or partially established in their target sites during embryogenesis:

• Waardenburg syndrome (types I, II, and III)

• Apert syndrome

• Pfeiffer syndrome

• Jackson-Weiss syndrome

• Crouzon syndrome

• Waardenburg syndrome type IV (Hirschsprung syndrome)

• Piebaldism

Patients with these congenital patterned leukodermas may also present with extrapigmentary findings consisting of megacolon and musculoskeletal defects of the face and upper trunk.

The unifying abnormality of these congenital patterned leukodermas is a complete or partial absence of melanocytes in the skin and hair. Mutations in genes that regulate the multistep process of commitment of neural crest cells to a differentiated cell type (primarily the melanocyte) are the basis for these diseases. These mutations result in a failure of melanocytes to reach their normal destinations in developing skin, hair, eyes, and ears during embryogenesis.[1, 2, 3, 4, 5, 6, 7]

The causes of these congenital patterned leukodermas are mutations in specific genes.[5, 8]

Type I and type III Waardenburg syndromes result from mutations in the PAX3 gene,[9] which maps to band 2q35-q37.3. The syndrome is inherited as an autosomal dominant trait. The PAX3 gene encodes a transcription factor with a paired box domain, an octapeptide domain, and a homeobox domain essential for survival of melanocytes during development. The genes up-regulated by this transcription factor have not been identified; however, the PAX3 gene product can bind to the promoter of the MITF gene.[6, 10, 11, 12, 13]

Type II Waardenburg syndrome results from mutations in the microphthalmia transcription factor (MITF) gene,[14] which maps to band 3p12. The syndrome is inherited as an autosomal dominant trait. The MITF gene encodes a transcription factor containing a basic-helix-loop-helix-leucine zipper. The genes up-regulated by this transcription factor during embryogenesis have not been identified.[15]

Type IV Waardenburg syndrome (Hirschsprung syndrome) results from mutations in either (1) the SOX10 gene, which maps to band 22q13, or (2) the EDN3 gene, which maps to band 20q13.2-q13.3. The SOX10 gene encodes a member of the high-mobility group-domain Sox family of transcription factors that regulate neural crest development. The genes up-regulated by this transcription factor during embryogenesis have not been identified; however, the SOX10 gene product can bind to the promoter of the MITF gene. The EDN3 gene encodes a ligand called endothelin-3 for the endothelin-B receptor.[10, 11, 16, 17]

Apert, Pfeiffer, Jackson-Weiss, and Crouzon syndromes result from mutations in the fibroblast growth factor receptor-2 (FGFR2) gene, which maps to band 10q25-q26. These syndromes are inherited as autosomal dominant traits. The FGFR2 gene encodes a tyrosine kinase receptor with 3 immunoglobulin domains, a signal sequence, an acidic region in the extracellular ligand binding site, and 2 tyrosine kinase domains localized intracellularly. Some patients with Pfeiffer syndrome have demonstrated mutations in the fibroblast growth factor receptor-1 (FGFR1) gene, which maps to band 8p11.2-12.[18, 19]

Hirschsprung syndrome type 2 results from mutations in the endothelin-B receptor (EDNRB) gene, which maps to band 13q22. This syndrome is inherited as an autosomal recessive trait. The EDNRB gene encodes a G protein–coupled plasma membrane receptor with 7 transmembrane domains and 2 autophosphorylation sites.

Piebaldism results from mutations in the c-KIT gene, which maps to band 4q12. This syndrome is inherited as an autosomal dominant trait. The KIT gene encodes a plasma membrane receptor with a ligand-binding domain containing 5 immunoglobulinlike regions and 2 tyrosine kinase domains in the cytoplasm. Specific mutations of c-KIT correlate with the severity (ie, extent) of the cutaneous hypopigmentation.[10, 20, 21, 22] According to Yang et al, deletion of the SNAI2 gene causes human piebaldism.[7]

Frequency

The approximate prevalences of the listed congenital patterned leukodermas are as follows:

• Waardenburg syndrome (types I, II, and III) - 1 case per 15,000 population

• Apert syndrome - 1 case per 65,000 population

• Pfeiffer syndrome - Unknown (rare)

• Jackson-Weiss syndrome - Unknown (rare)

• Crouzon syndrome - 1 case per 25,000 population

• Waardenburg syndrome type IV (Hirschsprung syndrome) - 1 case per 5000 population

• Piebaldism – Unknown (rare)

Race

All races appear to be equally affected by the associated mutations in congenital patterned leukodermas.

Sex

The prevalence of these congenital patterned leukodermas is equal for males and females.

Age

All of these congenital patterned leukodermas are present at birth.

In the congenital patterned leukodermas, an absence of protective pigment in the skin results in increased sensitivity to solar irradiation. Affected individuals may be at increased risk of developing skin cancers. Sensorineural deafness can be extensive in patients with Waardenburg syndromes and Hirschsprung syndrome but is usually minimal or absent in those with Apert, Pfeiffer, Jackson-Weiss, or Crouzon syndromes. Persons with piebaldism only rarely have sensorineural deafness. Visual acuity does not appear to be impaired in any of the syndromes.

Persons with type I Waardenburg syndrome present with unpigmented macules of the skin varying markedly in size and number. Associated with the cutaneous amelanosis are heterochromic irides that can be partial and/or unilateral (bichromia), sensorineural deafness with the absence or reduction of melanocytes in the cochlea, and dystopia canthorum, which manifests as a broadening of the base of the nose.[23]

Persons with type II Waardenburg syndrome present with features similar to those with type I Waardenburg, but they lack dystopia canthorum.

Persons with type III Waardenburg syndrome present with the same features as those with type I Waardenburg syndrome but with additional musculoskeletal abnormalities of the face and upper torso.

Persons with type IV Waardenburg syndrome present with variable cutaneous hypopigmentation, cochlear neurosensory deafness, and enteric aganglionosis, similar to persons with Hirschsprung syndrome.[24, 25]

Persons with Apert syndrome present with craniosynostosis (premature fusion of cranial sutures), craniofacial anomalies, and asymmetric syndactyly of both the hands and the feet.[26, 27] Cutaneous and ocular hypopigmentation is readily apparent in approximately 27% of people with Apert syndrome.

Persons with Pfeiffer syndrome present with craniosynostosis and broadening of the greater toes and thumbs. Cutaneous hypopigmentation occurs in approximately 10%.[28]

Persons with Jackson-Weiss syndrome present with craniosynostosis, wide feet, and normal hands.

Persons with Crouzon syndrome present with cranial defects only. (Apparent cutaneous hypopigmentation has not been described in people with Jackson-Weiss or Crouzon syndromes.)

Persons with Waardenburg syndrome type IV (Hirschsprung syndrome) primarily present with congenital aganglionic megacolon. This syndrome results from the absence of neural crest cells in the colon with the subsequent failure to form Meissner and Auerbach autonomic plexuses in the intestinal smooth muscle wall. Hirschsprung syndrome, in many people, is associated with hypopigmentation of varying extent, heterochromic irides, and deafness.

Persons with piebaldism present with cutaneous amelanosis ranging from only a small, white forelock with minimal ventral unpigmented areas to an almost total lack of skin and hair pigmentation. Rarely, the melanocytes in the eye or ear are affected.

Limited medical treatment is available for abnormalities of the skin, hair, eyes, or ears that result from a paucity or absence of melanocytes. Surgical skin-grafting techniques have been developed, with variable success in establishing pigmentation. Camouflaging involved areas with skin stains or sunless self-tanning agents may be helpful to some patients. The use of sunscreens and clothing is recommended to protect against ultraviolet light–induced skin damage.

Surgery may be necessary to correct extensive craniofacial defects in patients with Waardenburg or Apert syndromes.

Colostomy may be necessary in patients with Hirschsprung syndrome and aganglionic megacolon.

Patients with congenital patterned leukodermas should be screened for skin cancer.

Patients with congenital patterned leukodermas should be routinely followed for advancement of the nonpigmentary disorders.